Aportación de la UE:

Coordinado en:

Tema(s):

Convocatoria de propuestas:

Régimen de financiación:

EIF - Marie Curie actions-Intra-European Fellowships

Objetivo

The interaction between aromatic ligands (e.g. daunomycin) and deoxyribonucleic acid (DNA) has been the object of considerable research in connection with the use of such molecules as anti-cancer drugs. Drug design usually aims to exploit the specificity of gene sequence in the cell DNA, since diseases are often connected with gene defects.

The action of the ligand (i.e. drug) has been interpreted as an intercalation into the DNA structure with some unknown binding mechanism lengthening the helix. To the best of our knowledge a microscopic interpretation of the mechanism and rate based on the dynamics of the ligand-DNA interactions is still lacking. We thus propose a complete theoretical investigation of the mechanism of the intercalation which considers the effects of the molecular nature of the drug and of the portion of DNA exposed to the ligand action.

The goal of this research is to provide a molecular understanding of and a predictive theory for rational improvement of drug design. In addition to the value of the project in the biomedical field and therefore in the development of European research concerning anti-cancer drugs, an advanced training in multi-disciplinary subjects will be necessarily provided to the fellow in her chosen field of future research. Intercalation is in fact a complex process involving the motion of the ligand and the local DNA structure (which must change to accommodate the drug) and rearrangement of surrounding solvent and ion molecules.

A multi-dimensional free energy surface, constructed via electronic structure calculations and Molecular Dynamics computer simulations, and a generalized Langevin description approach will be employed to analyze the dynamics of the motion leading to the binding and to construct an explicit theory for the intercalation rate constant. Particular attention will be paid to the key drug-DNA interactions involved and to the influence of changing the base sequence, critical factors for the intercalation.